Discrimination against differently abled children among rural communities in India: Need for action.
Persons with disabilities comprise at least 4 to 8 percent of the Indian population. Children with disabilities in India are subject to multiple deprivations and limited opportunities in several dimensions of their lives. Their families and caregivers also go through lot of stress and challenges in having a person with disability at home which ultimately leads to grave discriminatory practices towards these children. The article attempts to analyze and describe the common discriminatory grounds that children with disabilities commonly face from their immediate families and from the larger community through analyzing the filed visit reports of the Basic Needs India Staff providing on job training (handholding support) for the community based rehabilitation workers. The case studies describes the various ugly forms of the discriminatory practices seen in the community towards differently abled children, same been categorized as denial of disability, physical restraints, social boycott, denial of property rights, decreased marital life prospects due to disabled member in family, implications on sexuality of people with disability, women with disability, discrepancies in state welfare programs, and problems in measuring disabilities. During the last two decades, there has been a growing realization that institutional care for the disabled is not entirely suitable for their individual needs, dignity and independence. A movement towards community based rehabilitation has picked up pace and contribute toward greater independence and self sustainability of the disabled.


Singing in the brain: Neural representation of music and voice as revealed by fMRI.
The ubiquity of music across cultures as a means of emotional expression, and its proposed evolutionary relation to speech, motivated researchers to attempt a characterization of its neural representation. Several neuroimaging studies have reported that specific regions in the anterior temporal lobe respond more strongly to music than to other auditory stimuli, including spoken voice. Nonetheless, because most studies have employed instrumental music, which has important acoustic distinctions from human voice, questions still exist as to the specificity of the observed "music-preferred" areas. Here, we sought to address this issue by testing 24 healthy young adults with fast, high-resolution fMRI, to record neural responses to a large and varied set of musical stimuli, which, critically, included a capella singing, as well as purely instrumental excerpts. Our results confirmed that music; vocal or instrumental, preferentially engaged regions in the superior STG, particularly in the anterior planum polare, bilaterally. In contrast, human voice, either spoken or sung, activated more strongly a large area along the superior temporal sulcus. Findings were consistent between univariate and multivariate analyses, as well as with the use of a "silent" sparse acquisition sequence that minimizes any potential influence of scanner noise on the resulting activations. Activity in music-preferred regions could not be accounted for by any basic acoustic parameter tested, suggesting these areas integrate, likely in a nonlinear fashion, a combination of acoustic attributes that, together, result in the perceived musicality of the stimuli, consistent with proposed hierarchical processing of complex auditory information within the temporal lobes.


Prevalence and radiologic and histologic appearance of vesicourachal diverticula in dogs without clinical signs of urinary tract disease.
To determine prevalence and radiologic and histologic appearance of vesicourachal diverticula in dogs without clinical signs of urinary tract disease. Original study. 50 dogs between 4 months and 17 years old representing 22 breeds that had been euthanatized for unrelated reasons; none of the dogs had a history or clinical signs of urinary tract disease. Retrograde positive-contrast radiography was performed, and radiographs were examined for macroscopic diverticula. Necropsy specimens from the urinary bladder vertex were examined by means of light microscopy for diverticula and signs of inflammation. 17 of the 50 (34%) dogs had vesicourachal diverticula, and 1 additional dog had a urachal cyst. Fifteen of the 17 diverticula were macroscopic; surface area of the diverticulum could be measured radiographically in 13 of these dogs and ranged from 1 to 90 mm2. The remaining 2 diverticula were microscopic. Sixteen diverticula were intramural and 1 was extramural. Light microscopic signs of bladder wall inflammation could be detected in 5 dogs, 4 of which had macroscopic diverticula. Results suggest that a high percentage of dogs without clinical signs of urinary tract disease may have vesicourachal [corrected] diverticula. Further studies are needed to determine the clinical relevance of vesicourethral diverticula in dogs.


Changes in androgens during treatment with four low-dose contraceptives.
The aim of the present study was to compare changes in the endogenous androgen environment in healthy women while on low-dose oral contraceptives (OCs). One-hundred healthy women were randomized to receive one of four OCs during six months: 21 tablets of Cilest, Femodeen, Marvelon, or Mercilon. During the luteal phase of the pretreatment cycle, body weight and blood pressure were recorded and the following parameters were measured: sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), testosterone (T), free testosterone (FT), 5 alpha-dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone-sulphate (DHEA-S) and 17 alpha-hydroxyprogesterone (170HP) while also the free androgen index (FAI) was calculated. Measurements were repeated during the 3rd week of pill intake in the 4th and the 6th pill month. There were no differences on body mass and blood pressure with the use of the four OCs. The mean serum DHEA-S decreased significantly in all groups though less in the Mercilon group when compared to Cilest and Marvelon (approximately 20% vs 45%). Mean serum SHBG and CBG increased significantly in all four groups approximately 250% and 100%, respectively. In each group CBG also increased significantly but less in women taking Mercilon (-75%) as compared to the others (-100%). Current low-dose OCs were found to have similar impact on the endogenous androgen metabolism with significant decreases of serum testosterone, DHT, A, and DHEA-S. They may be equally beneficial in women with androgen related syndromes such as acne and hirsutism.


Mimic Cochlear Implant Surgery-Induced Cochlear Infection Fails to Further Damage Auditory Pathway in Deafened Guinea Pigs.
BACKGROUND Kanamycin and subsequent furosemide administration was applied to the healthy guinea pigs to induce deafness. MATERIAL AND METHODS Of the deafened guinea pigs, 10 were further infused with anti-infection procedures (Group B) and the other 10 animals did not undergo anti-infection procedures (Group C). In Group B, the deafened animals were able to restore cochlear and middle ear functions following the anti-infection procedure. In Group C, all animals developed cochlear and middle ear infections. RESULTS Compared to the healthy guinea pigs, hair cells and spiral ganglion neurons (SGN) of deafened animals (in Group B and Group C) were severely damaged. SGN density of deafened animals was significantly lower than that of healthy control animals in all ear turns except the basal turn. There was no significant difference between Group B and Group C in SGN density. The average optical density value of neurofilaments of deafened animals was also significantly decreased after the ototoxic drug administration. Notably, the density of the neurons in the cochlear nucleus region (CNR) of the brainstem were not significantly different between the healthy control guinea pigs and deafened animals. CONCLUSIONS Mimic cochlear implant surgery-induced cochlear infection caused no significant damage to the auditory pathway in ototoxic drug-induced deafened guinea pigs.


Invasive validation of a new oscillometric device (Arteriograph) for measuring augmentation index, central blood pressure and aortic pulse wave velocity.
The importance of measuring aortic pulse wave velocity (PWVao), aortic augmentation index (Aix) and central systolic blood pressure (SBPao) has been shown under different clinical conditions; however, information on these parameters is hard to obtain. The aim of this study was to evaluate the accuracy of a new, easily applicable oscillometric device (Arteriograph), determining these parameters simultaneously, against invasive measurements. Aortic Aix, SBPao and PWVao were measured invasively during cardiac catheterization in 16, 55 and 22 cases, respectively, and compared with the values measured by the Arteriograph. We found strong correlation between the invasively measured aortic Aix and the oscillometrically measured brachial Aix on either beat-to-beat or mean value per patient basis (r = 0.9, P < 0.001; r = 0.94, P < 0.001), which allowed the noninvasive calculation of the aortic Aix without using generalized transfer function. Similarly strong correlation (r = 0.95, P < 0.001) was found between the invasively measured and the noninvasively calculated central SBPao; furthermore, the BHS assessment of the paired differences fulfilled the 'B' grading. The PWVao values measured invasively and by Arteriograph were 9.41 ± 1.8 m/s and 9.46 ± 1.8 m/s, respectively (mean ± SD); furthermore, the Pearson's correlation was 0.91 (P < 0.001). The limits of agreement were 11.4% for aortic Aix and 1.59 m/s for PWVao. Aix, SBPao and PWVao, measured oscillometrically, showed strong correlation with the invasively obtained values. The observed limits of agreement are encouragingly low for accepting the method for clinical use. Our results suggest that the PWVao values, measured by Arteriograph, are close to the true aortic PWV, determined invasively.


A canonical circuit for generating phase-amplitude coupling.
'Phase amplitude coupling' (PAC) in oscillatory neural activity describes a phenomenon whereby the amplitude of higher frequency activity is modulated by the phase of lower frequency activity. Such coupled oscillatory activity--also referred to as 'cross-frequency coupling' or 'nested rhythms'--has been shown to occur in a number of brain regions and at behaviorally relevant time points during cognitive tasks; this suggests functional relevance, but the circuit mechanisms of PAC generation remain unclear. In this paper we present a model of a canonical circuit for generating PAC activity, showing how interconnected excitatory and inhibitory neural populations can be periodically shifted in to and out of oscillatory firing patterns by afferent drive, hence generating higher frequency oscillations phase-locked to a lower frequency, oscillating input signal. Since many brain regions contain mutually connected excitatory-inhibitory populations receiving oscillatory input, the simplicity of the mechanism generating PAC in such networks may explain the ubiquity of PAC across diverse neural systems and behaviors. Analytic treatment of this circuit as a nonlinear dynamical system demonstrates how connection strengths and inputs to the populations can be varied in order to change the extent and nature of PAC activity, importantly which phase of the lower frequency rhythm the higher frequency activity is locked to. Consequently, this model can inform attempts to associate distinct types of PAC with different network topologies and physiologies in real data.


The Trichoplax genome and the nature of placozoans.
As arguably the simplest free-living animals, placozoans may represent a primitive metazoan form, yet their biology is poorly understood. Here we report the sequencing and analysis of the approximately 98 million base pair nuclear genome of the placozoan Trichoplax adhaerens. Whole-genome phylogenetic analysis suggests that placozoans belong to a 'eumetazoan' clade that includes cnidarians and bilaterians, with sponges as the earliest diverging animals. The compact genome shows conserved gene content, gene structure and synteny in relation to the human and other complex eumetazoan genomes. Despite the apparent cellular and organismal simplicity of Trichoplax, its genome encodes a rich array of transcription factor and signalling pathway genes that are typically associated with diverse cell types and developmental processes in eumetazoans, motivating further searches for cryptic cellular complexity and/or as yet unobserved life history stages.


The short-term role of corticosteroid therapy for pulmonary arterial hypertension associated with connective tissue diseases: report of five cases and a literature review.
Pulmonary arterial hypertension (PAH) is a life-threatening complication in connective tissue diseases (CTD). It remains controversial whether immunosuppressive therapy is useful for PAH associated with CTD (PAH-CTD). The Dana Point algorithm does not refer such treatments in patients with PAH-CTD due to the lack of evidence. However, some case reports have shown the potential efficacy of immunosuppression for PAH-CTD. Here we report five cases of PAH-CTD treated with corticosteroids and discuss the current management of PAH-CTD with immunosuppressive agents. Our cases consisted of three active systemic lupus erythematosus (SLE), a quiescent SLE and an active polymyositis. WHO functional classes at baseline were class III in three cases and class II in two. Median follow-up period was 44 (28-92) weeks. PAH was diagnosed by right heart catheterization in all cases (median pulmonary arterial pressure was 45 (29-49) mmHg). All patients received 1 mg/kg of prednisolone (PSL) for 2-4 weeks, followed by appropriate dose reduction. Methylprednisolone pulse therapy was performed in patients resistant to the high dosage of PSL. Four patients received vasodilators in combination. The therapy as above improved WHO functional class 4 weeks after the initiation of PSL in all the patients. Two patients required dose increase or additional administration of vasodilators due to the dose reduction of PSL. Corticosteroid therapy may be effective for PAH-CTD at least in the short term, even in low general activity of CTD or moderate PAH. Our experience suggests that corticosteroid therapy, by itself or in conjunction with standard vasodilators, is effective for PAH-CTD patients.


Treating insomnia improves mood state, sleep, and functioning in bipolar disorder: a pilot randomized controlled trial.
To determine if a treatment for interepisode bipolar disorder I patients with insomnia improves mood state, sleep, and functioning. Alongside psychiatric care, interepisode bipolar disorder I participants with insomnia were randomly allocated to a bipolar disorder-specific modification of cognitive behavior therapy for insomnia (CBTI-BP; n = 30) or psychoeducation (PE; n = 28) as a comparison condition. Outcomes were assessed at baseline, the end of 8 sessions of treatment, and 6 months later. This pilot was conducted to determine initial feasibility and generate effect size estimates. During the 6-month follow-up, the CBTI-BP group had fewer days in a bipolar episode relative to the PE group (3.3 days vs. 25.5 days). The CBTI-BP group also experienced a significantly lower hypomania/mania relapse rate (4.6% vs. 31.6%) and a marginally lower overall mood episode relapse rate (13.6% vs. 42.1%) compared with the PE group. Relative to PE, CBTI-BP reduced insomnia severity and led to higher rates of insomnia remission at posttreatment and marginally higher rates at 6 months. Both CBTI-BP and PE showed statistically significant improvement on selected sleep and functional impairment measures. The effects of treatment were well sustained through follow-up for most outcomes, although some decline on secondary sleep benefits was observed. CBTI-BP was associated with reduced risk of mood episode relapse and improved sleep and functioning on certain outcomes in bipolar disorder. Hence, sleep disturbance appears to be an important pathway contributing to bipolar disorder. The need to develop bipolar disorder-specific sleep diary scoring standards is highlighted.


[Effects of irbesartan on remodeling of the left ventricular following acute myocardial infarction].
To compare the inhibitory effects of irbesartan on left ventricular remodeling (LVRM) after acute myocardial infarction (AMI). A total of 72 patients with AMI were entered into the study, 36 patients were randomized to conventional treatment group, and 36 patients to irbesartan treatment group. At 2nd week and 24th week after AMI, the left ventricular myocardium weight was measured by echocardiogram, and the parameters of left ventricular systolic and diastolic function were measured by equilibrium radionuclide angiography. At 24th week, interventricular septal thickness (IVST), left ventricular posterior wall thick(LVPWT), left ventricular diastolic diameter (LVDd) and left ventricular mass index(LVMI) in irbesartan treatment group were significantly decreased(P<0.05 or P<0.01) compared with conventional treatment group At 24th week, left ventricular ejection fraction(LVEF), left ventricular peak ejecting rate (LPER) and left ventricular peak filling rate (LPFR) in irbesartan treatment group were significantly increased (P<0.05 or P<0.01) compared with those in conventional treatment group, respectively. Left ventricular time of peak ejecting rate (LTPER) and left ventricular time of peak filling rate (LTPFR) in irbesartan group were decreased(P<0.05 or P<0.01) compared with the conventional treatment group, respectively. Irbesartan might significantly reduce myocardial hypertrophy and LVRM after AMI. Irbesartan improves the left ventricular systolic function.


Mie resonances of dielectric spheres in face-centered cubic photonic crystals.
With use of plane waves as a basis for the band-structure calculation of a periodic assembly of highly refringent microspheres, it can be shown that resonance-mode frequencies of isolated dielectric spheres show up in the band structures. The strongly localized bands provided by the photonic-crystal analysis is compared with exact calculations made in spherical symmetry for an isolated microsphere. This comparison sheds some light on the effectiveness of the methods based on the description of mode coupling and, in particular, on the validity of tight-binding approaches of the description of photonic band structures. In addition, examining the effect of modifying the distance separating the spheres in the lattice, makes it easy to visualize the overlap between the modes of individual spheres. Thus quantitative information is provided on the geometry needed to feed energy into low-angular-momentum morphology-dependent resonances from a sharp source of the evanescent field and on the lifetime of these modes, when the resonances are disturbed by the proximity of a dielectric object of similar radius.


Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation.
The shelterin complex plays dual functions in telomere homeostasis by recruiting telomerase and preventing the activation of a DNA damage response at telomeric ends. Somatic stem cells require telomerase activity, as evidenced by progressive stem cell loss leading to bone marrow failure in hereditary dyskeratosis congenita. Recent work demonstrates that dyskeratosis congenita can also arise from mutations in specific shelterin genes, although little is known about shelterin functions in somatic stem cells. We found that mouse hematopoietic stem cells (HSCs) are acutely sensitive to inactivation of the shelterin gene Acd, encoding TPP1. Homozygosity for a hypomorphic acd allele preserved the emergence and expansion of fetal HSCs but led to profoundly defective function in transplantation assays. Upon complete Acd inactivation, HSCs expressed p53 target genes, underwent cell cycle arrest, and were severely depleted within days, leading to hematopoietic failure. TPP1 loss induced increased telomeric fusion events in bone marrow progenitors. However, unlike in epidermal stem cells, p53 deficiency did not rescue TPP1-deficient HSCs, indicating that shelterin dysfunction has unique effects in different stem cell populations. Because the consequences of telomere shortening are progressive and unsynchronized, acute loss of shelterin function represents an attractive alternative for studying telomere crisis in hematopoietic progenitors.


Characterization of an Adapted Murine Model of Intrauterine Inflammation-Induced Preterm Birth.
Preterm birth (PTB) affects nearly 15 million infants each year. Of these PTBs, >25% are a result of inflammation or infection. Animal models have improved our understanding of the mechanisms leading to PTB. Prior work has described induction of intrauterine inflammation in mice with a single injection of lipopolysaccharide (LPS). Herein, we have improved the reproducibility and potency of LPS in the model using two injections distal to the cervix. An in vivo imaging system revealed more uniform distribution of Evans Blue Dye using a double distal injection (DDI) approach compared with a single proximal injection (SPI). Endotoxin concentrations in vaginal lavage fluid from SPI dams were significantly higher than from DDI dams. At equivalent LPS doses, DDI consistently induced more PTB than SPI, and DDI showed a linear dose-response, whereas SPI did not. Gene expression in myometrial tissue revealed increased levels of inflammatory markers in dams that received LPS DDI compared with LPS SPI. The SPI group showed more significant overexpression in cervical remodeling genes, likely due to the leakage of LPS from the uterine horns through the cervix. The more reliable PTB induction and uniform uterine exposure provided by this new model will be useful for further studying fetal outcomes and potential therapeutics for the prevention of inflammation-induced PTB.


Reduced stimulation of recombinant DNA polymerase γ and mitochondrial DNA (mtDNA) helicase by variants of mitochondrial single-stranded DNA-binding protein (mtSSB) correlates with defects in mtDNA replication in animal cells.
The mitochondrial single-stranded DNA-binding protein (mtSSB) is believed to coordinate the functions of DNA polymerase γ (pol γ) and the mitochondrial DNA (mtDNA) helicase at the mtDNA replication fork. We generated five variants of the human mtSSB bearing mutations in amino acid residues specific to metazoans that map on the protein surface, removed from the single-stranded DNA (ssDNA) binding groove. Although the mtSSB variants bound ssDNA with only slightly different affinities, they exhibited distinct capacities to stimulate the DNA polymerase activity of human pol γ and the DNA unwinding activity of human mtDNA helicase in vitro. Interestingly, we observed that the variants with defects in stimulating pol γ had unaltered capacities to stimulate the mtDNA helicase; at the same time, variants showing reduced stimulation of the mtDNA helicase activity promoted DNA synthesis by pol γ similarly to the wild-type mtSSB. The overexpression of the equivalent variants of Drosophila melanogaster mtSSB in S2 cells in culture caused mtDNA depletion under conditions of mitochondrial homeostasis. Furthermore, we observed more severe reduction of mtDNA copy number upon expression of these proteins during recovery from treatment with ethidium bromide, when mtDNA replication is stimulated in vivo. Our findings suggest that mtSSB uses distinct structural elements to interact functionally with its mtDNA replisome partners and to promote proper mtDNA replication in animal cells.


Gating deficits in model networks: a path to schizophrenia?
Gating deficits and hallucinatory sensations are prominent symptoms of schizophrenia. Comparing these abnormalities with the failure modes of network models is an interesting way to explore how they arise. We present a network model that can both propagate and gate signals. The model exhibits effects reminiscent of clinically observed pathologies when the balance between excitation and inhibition that it requires is not properly maintained.


Dealing with indeterminate outcomes in antimalarial drug efficacy trials: a comparison between complete case analysis, multiple imputation and inverse probability weighting.
Antimalarial clinical efficacy studies for uncomplicated Plasmodium falciparum malaria frequently encounter situations in which molecular genotyping is unable to discriminate between parasitic recurrence, either new infection or recrudescence. The current WHO guideline recommends excluding these individuals with indeterminate outcomes in a complete case (CC) analysis. Data from the four artemisinin-based combination (4ABC) trial was used to compare the performance of multiple imputation (MI) and inverse probability weighting (IPW) against the standard CC analysis for dealing with indeterminate recurrences. 3369 study participants from the multicentre study (4ABC trial) with molecularly defined parasitic recurrence treated with three artemisinin-based combination therapies were used to represent a complete dataset. A set proportion of recurrent infections (10, 30 and 45%) were reclassified as missing using two mechanisms: a completely random selection (mechanism 1); missingness weakly dependent (mechanism 2a) and strongly dependent (mechanism 2b) on treatment and transmission intensity. The performance of MI, IPW and CC approaches in estimating the Kaplan-Meier (K-M) probability of parasitic recrudescence at day 28 was then compared. In addition, the maximum likelihood estimate of the cured proportion was presented for further comparison (analytical solution). Performance measures (bias, relative bias, standard error and coverage) were reported as an average from 1000 simulation runs. The CC analyses resulted in absolute underestimation of K-M probability of day 28 recrudescence by up to 1.7% and were associated with reduced precision and poor coverage across all the scenarios studied. Both MI and IPW method performed better (greater consistency and greater efficiency) compared to CC analysis. In the absence of censoring, the analytical solution provided the most consistent and accurate estimate of cured proportion compared to the CC analyses. The widely used CC approach underestimates antimalarial failure; IPW and MI procedures provided efficient and consistent estimates and should be considered when reporting the results of antimalarial clinical trials, especially in areas of high transmission, where the proportion of indeterminate outcomes could be large. The analytical solution estimating the cured proportion could provide an alternative approach, in scenarios with minimal censoring due to loss to follow-up or new infections.


The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study.
We report the results of a Phase I/II dose escalation study to determine the maximum tolerated dose (MTD) of cyclophosphamide when combined with lenalidomide and dexamethasone in relapsed/refractory myeloma. Thirty-one patients were enrolled in cohorts of 3, at five dose levels of cyclophosphamide to a maximum of 700 mg on days 1 and 8 of a 28-d cycle. Patients received lenalidomide 25 mg days 1-21 and dexamethasone 20 mg orally days 1-4 and 8-11. The MTD was 600 mg cyclophosphamide, days 1 and 8. Grade 3/4 haematological complications occurred in 26% of patients, grade 3/4 infection in 3% (both at 700 mg cyclophosphamide), with thromboembolic complications in 6% of patients. Overall complete response (CR) rate was 29%, very good partial response rate 7% and partial response rate 45% giving an overall response rate of 81%. After 21 months median follow-up, projected 2-year progression-free survival was 56%, with 80% overall survival at 30 months. Ten further patients were treated at MTD with a 40% CR rate. No dose reductions for any study drugs or deaths occurred during cycles 1-9. Lenalidomide, cyclophosphamide and dexamethasone is a safe, effective combination in relapsed myeloma inducing a high response rate, warranting further investigation in phase III trials.


Cytokine gene expression following neural grafts.
A reverse-transcription polymerase chain reaction study of molecular events following solid neural tissue xenogeneic and syngeneic grafts into the mouse caudate nucleus was made between 1 day and 30 days post-grafting. Constitutive expression of interleukin (IL)-1 and transforming growth factor (TGF)-beta1 mRNAs was detected. The sham operation produced minimal cytokine upregulation, indicating that surgical trauma caused minimal damage. A similar picture was seen with syngeneic grafts, which showed good graft survival. Xenografts, however, were rejected within 30 days and cytokine mRNAs for IL-2, IL-2R, IL-4, IL-10 and interferon (IFN)-gamma were detected from 7 days post-graft, correlating with histological identification of a leukocytic infiltrate. This method provides a quick, comparative screen for detecting cytokine mRNA profiles in neural grafts and may assist the diagnosis of early rejection phenomena. As such, it is a potential analytical tool for strategies aimed at depleting/blocking the activity of different cell types and/or cytokines in future neural transplant therapy.


Adaptive strategy for the statistical analysis of connectomes.
We study an adaptive statistical approach to analyze brain networks represented by brain connection matrices of interregional connectivity (connectomes). Our approach is at a middle level between a global analysis and single connections analysis by considering subnetworks of the global brain network. These subnetworks represent either the inter-connectivity between two brain anatomical regions or by the intra-connectivity within the same brain anatomical region. An appropriate summary statistic, that characterizes a meaningful feature of the subnetwork, is evaluated. Based on this summary statistic, a statistical test is performed to derive the corresponding p-value. The reformulation of the problem in this way reduces the number of statistical tests in an orderly fashion based on our understanding of the problem. Considering the global testing problem, the p-values are corrected to control the rate of false discoveries. Finally, the procedure is followed by a local investigation within the significant subnetworks. We contrast this strategy with the one based on the individual measures in terms of power. We show that this strategy has a great potential, in particular in cases where the subnetworks are well defined and the summary statistics are properly chosen. As an application example, we compare structural brain connection matrices of two groups of subjects with a 22q11.2 deletion syndrome, distinguished by their IQ scores.


North American and European porcine reproductive and respiratory syndrome viruses differ in non-structural protein coding regions.
Although North American and European serotypes of porcine reproductive and respiratory syndrome virus (PRRSV) are recognized, only the genome of the European Lelystad strain (LV) has been sequenced completely. Here, the genome of the pathogenic North American PRRSV isolate 16244B has been sequenced and compared with LV. The genomic organization of 16244B was the same as LV but with only 63.4% nucleotide identity. The 189 nucleotide 5' non-coding region (NCR) of 16244B was distinct from the LV NCR, with good conservation (83%) only over a 43 base region immediately upstream of open reading frame (ORF) 1a. Major differences were found in the region encoding the non-structural part of the ORF1a polyprotein, which shared only 47% amino acid identity over 2503 residues of the six non-structural proteins (Nsps) encoded. Nsp2, thought to have a species-specific function, showed the greatest divergence, sharing only 32% amino acid identity with LV and containing 120 additional amino acids in the central region. Nsps encoded by the 5'-proximal and central regions of ORF1b had from 66 to 75% amino acid identity; however, the carboxy-terminal protein CP4 was distinct (42% identity). The ORF 1a-1b frameshift region of 16244B had 98% nucleotide identity with LV. Consistent with previous reports for North American isolates, the six structural proteins encoded were 58 to 79% identical to LV proteins. The 3' NCR (150 nucleotides) was 76% identical between isolates. These genomic differences confirm the presence of distinct North American and European PRRSV genotypes.


Bacterial Tubulins: A Eukaryotic-Like Microtubule Cytoskeleton.
Ever since their discovery, bacterial tubulins, found in several Prosthecobacter species, have raised curiosity as they are closely related to eukaryotic tubulin. Deng and colleagues now present new evidence for the functional homology of the two cytoskeletal systems where in vitro reconstituted Btub-microtubules display eukaryote-like biochemical and dynamic properties.


Compositional contrast of biological materials in liquids using the momentary excitation of higher eigenmodes in dynamic atomic force microscopy.
Atomic Force microscope (AFM) cantilevers commonly used for imaging soft biological samples in liquids experience a momentary excitation of the higher eigenmodes at each tap. This transient response is very sensitive to the local sample elasticity under gentle imaging conditions because the higher eigenmode time period is comparable to the tip-sample contact time. By mapping the momentary excitation response, we demonstrate a new scanning probe spectroscopy capable of resolving with high sensitivity the variations in the elasticity of soft biological materials in liquids.


Expression of High Mobility Group Box 1 Protein in a Polytrauma Model During Ground Transport and Simulated High-Altitude Evacuation.
We investigated the expression of high mobility group box 1 (HMGB1) protein in a combat-relevant polytrauma/ acute respiratory distress syndrome (ARDS) model. We hypothesized that systemic HMGB1 expression is increased after injury and during aeromedical evacuation (AE) at altitude. Female Yorkshire swine (n =15) were anesthetized and cannulated with a 23Fr dual-lumen catheter. Venovenous extracorporeal life support (VV ECLS) was initiated via the right jugular vein and carried out with animals uninjured on day 1 and injured by bilateral pulmonary contusion on day 2. On both days, animals underwent transport and simulated AE. Systemic HMGB1 expression was measured in plasma by ELISA. Plasma-free Hb (pfHb) was measured with the use of spectrophotometric methods. Plasma HMGB1 on day 1 was transiently higher at arrival to the AE chambers, increased significantly after injury, reaching highest values at 8,000 ft on day 2, after which levels decreased but remained elevated versus baseline at each time point. pfHb decreased on day 1 at 30,000 ft and significantly increased on day 2 at 8,000 ft and postflight. Systemic HMGB1 demonstrated sustained elevation after trauma and altitude transport and may provide a useful monitoring capability during en route care.


Diagnosis, Prognosis, and Treatment of Alveolar Soft-Part Sarcoma: A Review.
Alveolar soft-part sarcoma (ASPS) is a rare, translocation-driven sarcoma of the soft tissues. Alveolar soft-part sarcoma often affects young adults and is characterized by indolent behavior but early evidence of metastatic spread. After recognition of ASPS as a specific entity in 1952, retrospective data indicated prolonged survival in patients with metastases, despite inherent resistance to conventional doxorubicin-based chemotherapy. Tyrosine kinase inhibitors and immune checkpoint inhibitors have provided unexpected new treatment strategies for ASPS. This review includes articles published between 1952 and March 1, 2018. With the introduction of new molecular diagnostic tools and therapies, the distinctive features of ASPS have become more evident. The identification and better understanding of molecular pathways activated by the characteristic t(X;17)(p11;q25) translocation and its correspondent chimeric ASPSCR1-transcription factor E3 (TFE3) fusion protein open new paths to drug development. The associations of TFE3 and facilitation of an immunosuppressive microenvironment provide a rationale for exploring treatments that affect the balance between T-effector cells and T-regulatory cells. Tyrosine kinase inhibitors, such as sunitinib, cediranib, and pazopanib, show activity with either tumor responses or disease stabilization in more than 50% of the cases. Given the association of new agents with patient outcomes, it is too early to say whether metastatic ASPS should still be considered incurable in all patients. The biologic outcomes of the canonical genomic event in ASPS remain under investigation; a better understanding of the tumor microenvironment and the multiple pathways activated in this sarcoma, including unusual bioenergetics, MET signaling, and angiogenesis, should lead to more rational therapy. Basket trials and related prospective studies focusing on the intersection of specific signaling pathways and diseases with unique genomic features, such as ASPS, will provide an understanding of new options for care.


Density functional study of dendrimer molecules in solvents of varying quality.
Modified inhomogeneous statistical associating fluid theory (iSAFT) density functional theory is extended to dendrimer molecules in solvents of varying quality. The detailed structures of isolated dendrimers in implicit solvent are calculated and have a semi-quantitative agreement with simulation results available in the literature. The dendrimers form dense-core structures under all conditions, while their radius of gyration follows different scaling laws. Factors that affect the quality of the solvent are systematically studied in the explicit solvent case. It is found that the solvent size, density, chemical affinity and temperature all play a role in determining a solvent to be good or poor. New molecular dynamics simulations are performed to validate the iSAFT results. Our results provide insight into the phase behavior of dendrimer solutions as well as guidance in practical applications.


Mitochondrial disease.
Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. This review updates the topic of mitochondrial diseases by reviewing the most important recent advances in this area. The factors influencing inheritance, maintenance and replication of mtDNA are reviewed and the genotype-phenotype of mtDNA disorders has been expanded, with new insights into epidemiology, pathogenesis and its role in ageing. Recently identified nuclear gene mutations of mitochondrial proteins include mutations of frataxin causing Friedreich's ataxia, PINK1, DJ1 causing Parkinson's disease and POLG causing infantile mtDNA depletion syndrome, ophthalmoplegia, parkinsonism, male subfertility and, in a transgenic mouse model, premature senescence. Mitochondrial defects in neurodegenerative diseases include Parkinson's, Alzheimer's and Huntington's disease. Improved understanding of mtDNA inheritance and mutation penetrance patterns, and novel techniques for mtDNA modification offer significant prospects for more accurate genetic counselling and effective future therapies.


Statistics of natural images as a function of dynamic range.
The statistics of real world images have been extensively investigated, but in virtually all cases using only low dynamic range image databases. The few studies that have considered high dynamic range (HDR) images have performed statistical analyses categorizing images as HDR according to their creation technique, and not to the actual dynamic range of the underlying scene. In this study we demonstrate, using a recent HDR dataset of natural images, that the statistics of the image as received at the camera sensor change dramatically with dynamic range, with particularly strong correlations with dynamic range being observed for the median, standard deviation, skewness, and kurtosis, while the one over frequency relationship for the power spectrum breaks down for images with a very high dynamic range, in practice making HDR images not scale invariant. Effects are also noted in the derivative statistics, the single pixel histograms, and the Haar wavelet analysis. However, we also show that after some basic early transforms occurring within the eye (light scatter, nonlinear photoreceptor response, center-surround modulation) the statistics of the resulting images become virtually independent from the dynamic range, which would allow them to be processed more efficiently by the human visual system.


Optimal acetabular component orientation estimated using edge-loading and impingement risk in patients with metal-on-metal hip resurfacing arthroplasty.
Edge-loading in patients with metal-on-metal resurfaced hips can cause high serum metal ion levels, the development of soft-tissue reactions local to the joint called pseudotumours and ultimately, failure of the implant. Primary edge-loading is where contact between the femoral and acetabular components occurs at the edge/rim of the acetabular component whereas impingement of the femoral neck on the acetabular component's edge causes secondary or contrecoup edge-loading. Although the relationship between the orientation of the acetabular component and primary edge-loading has been identified, the contribution of acetabular component orientation to impingement and secondary edge-loading is less clear. Our aim was to estimate the optimal acetabular component orientation for 16 metal-on-metal hip resurfacing arthroplasty (MoMHRA) subjects with known serum metal ion levels. Data from motion analysis, subject-specific musculoskeletal modelling and Computed Tomography (CT) measurements were used to calculate the dynamic contact patch to rim (CPR) distance and impingement risk for 3416 different acetabular component orientations during gait, sit-to-stand, stair descent and static standing. For each subject, safe zones free from impingement and edge-loading (CPR <10%) were defined and, consequently, an optimal acetabular component orientation was determined (mean inclination 39.7° (SD 6.6°) mean anteversion 14.9° (SD 9.0°)). The results of this study suggest that the optimal acetabular component orientation can be determined from a patient's motion and anatomy. However, 'safe' zones of acetabular component orientation associated with reduced risk of dislocation and pseudotumour are also associated with a reduced risk of edge-loading and impingement.


Nampt secreted from cardiomyocytes promotes development of cardiac hypertrophy and adverse ventricular remodeling.
Nicotinamide phosphoribosyltransferase (Nampt) is an important coenzyme involved in cellular redox reactions. Inside the cell, Nampt (iNampt) functions as a rate-limiting enzyme in the NAD salvage pathway, and outside the cell (eNampt), it acts as a proinflammatory cytokine. High-circulating levels of Nampt are reported in different pathological conditions. This study was designed to examine the role of Nampt in the development of cardiac hypertrophy and ventricular remodeling. We studied the hypertrophic response in Nampt heterozygous (+/-) knockout and cardiac-specific overexpressing Nampt transgenic mice. Whereas Nampt(+/-) mice were protected against agonist (isoproterenol and angiotensin II)-induced hypertrophy, Nampt transgenic mice spontaneously developed cardiac hypertrophy at 6 mo of age. Experiments conducted to gain insight into the mechanism revealed that treatment of cardiomyocytes with recombinant (eNampt) or overexpression with Nampt-synthesizing adenovirus vector (Ad.Nampt) induced cardiomyocyte hypertrophy. The prohypertrophic effects of eNampt and Ad.Nampt were blocked by the addition of a Nampt-blocking antibody into cultures, thus suggesting that Nampt was in fact invoking hypertrophic response of cardiomyocytes by acting on the cell surface receptors. We also found increased Nampt levels in the supernatant of cardiomyocyte cultures subjected to stress by either serum starvation or H(2)O(2) treatment. Exploration of signaling pathways in Nampt-induced cardiac hypertrophy and fibrosis revealed increased activation of mitogen-activated protein kinases, namely, JNK1, p38, and ERK. This was also associated with increased calcineurin levels and nuclear factor of activated T-cell localization into the nucleus. From these studies we conclude that cardiomyocytes are capable of secreting Nampt during stress, and exogenous Nampt is a positive regulator of cardiac hypertrophy and adverse ventricular remodeling.


A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males.
The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2(-/-) mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2(-/-) mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct "modules," or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2(-/-) mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2(-/-) mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.


Correlates of parental antibiotic knowledge, demand, and reported use.
Clinicians cite parental misconceptions and requests for antibiotics as reasons for inappropriate prescribing. To identify misconceptions regarding antibiotics and predictors of parental demand for antibiotics and to determine if parental knowledge and attitudes are associated with use. Survey of parents in 16 Massachusetts communities. Domains included antibiotic-related knowledge, attitudes about antibiotics, antibiotic use during a 12-month period, demographics, and access to health information. Bivariate and multivariate analyses evaluated predictors of knowledge and proclivity to demand antibiotics. A multivariate model evaluated the associations of knowledge, demand, and demographic factors with parent-reported antibiotic use. A total of 1106 surveys were returned (response rates: 54% and 32% for commercially-insured and Medicaid-insured families). Misconceptions were common regarding bronchitis (92%) and green nasal discharge (78%). Two hundred sixty-five (24%) gave responses suggesting a proclivity to demand antibiotics. Antibiotic knowledge was associated with increased parental age and education, having more than 1 child, white race, and receipt of media information on resistance. Factors associated with a proclivity to demand antibiotics included decreased knowledge, pressure from day-care settings, lack of alternatives offered by clinicians, and lack of access to media information. Among all respondents, reported antibiotic use was associated with younger child age and day-care attendance. Among Medicaid-insured children only, less antibiotic knowledge and tendency to demand antibiotics were associated with higher rates of antibiotic use. Misconceptions regarding antibiotic use are widespread and potentially modifiable by clinicians and media sources. Particular attention should be paid to Medicaid-insured patients in whom such misconceptions may contribute to inappropriate prescribing.


Vicariance, colonisation, and fast local speciation in Asia Minor and the Balkans as revealed from the phylogeny of spined loaches (Osteichthyes; Cobitidae).
We reconstruct the phylogeny of the morphologically diagnosable subgenera Bicanestrinia, Beysehiria, and Cobitis sensu stricto of the genus Cobitis from Asia Minor and the Balkans. We used the complete cytochrome b gene of 65 specimens in order to infer their evolutionary history in this zoogeographically interesting area. Our phylogeographic analysis did not evidence the previously suggested monophyly of the Bicanestrinia subgenus but revealed five monophyletic lineages in the area: the lineages Bicanestrinia I-IV including all species of Bicanestrinia plus the lineage Cobitis s. str. The monotypic subgenus Beysehiria from Lake Beysehir in Anatolia was closely related to the syntopic population of C. turcica and nested inside the lineage Bicanestrinia III. The strictly allopatric distribution of the four lineages of Bicanestrinia suggests that vicariance has played a major role in the diversification of Bicanestrinia. All analysed species of Cobitis s. str. from Asia Minor and Balkans were closely related to Cobitis s. str. from Central Europe, the Danube basin and the Caucasus, indicating at least two colonisation events into Asia Minor and the Balkans. A third, recent colonisation event led to the presence of C. strumicae, generally restricted to the Aegean Sea drainage, in the Danube basin. Besides the evidences of vicariance and colonisation events in the phylogenetic history of the genus Cobitis in Asia Minor and the Balkans, our analysis suggested also a rapid morphological evolution of C. bilseli in a lacustrine environment. Application of Cobitis mitochondrial cytochrome b clocks of 0.68% sequence divergence per million years (MY) suggest that the split between the five major lineages happened approximately 12.4-17.6 MYA, and according to the lack of basal resolution of this monophyletic group probably the split of all lineages happened within a narrow time window.


Solubilization of aromatic and hydrophobic moieties by arginine in aqueous solutions.
Experiments hold intriguing, circumstantial clues to the mechanisms behind arginine-mediated solubilization of small organic drugs and suppression of protein aggregation driven by hydrophobic or aromatic associations, but how exactly arginine's molecular structure and interactions contribute to its function remains unclear since attention has focused so far on the thermodynamics of the preferential exclusion or binding of arginine. Here, we examine, through molecular dynamics simulations, how arginine solubilizes nanoscale particles with hydrophobic surfaces or aromatic-ring-type surface interactions. We show that preferential, hydrophobic, and dispersion interactions of arginine's guanidinium group with the particles lead to a surfactant-like behavior of arginine around the particles and to a solvation layer with a protective polar mask creating a hydrophilic shell. Additionally, arginine-arginine association around the solvation layer further prevents aggregative contacts. The results shed some light on the mechanistic basis of arginine's function as a suppressant of protein aggregation, although the complex energy landscapes and kinetic pathways of aggregation are protein-dependent and pose formidable challenges to developing comprehensive mechanistic pictures. Our results suggest arginine's mode of interaction with hydrophobic patches and aromatic residues could reduce aggregation-prone intermediate states of proteins and shield protein-protein aggregative contacts. The approach used here offers a systematic way of exploring implications of other amino acid/excipient interactions by studying interactions of the excipient with particles grafted with amino acids.


Penicillin-binding proteins of penicillin-susceptible and intrinsically resistant Neisseria gonorrhoeae.
The penicillin-binding proteins (PBPs) of Neisseria gonorrhoeae were investigated by using [3H]benzylpenicillin of high specific activity. This made it possible to label the PBPs both in cytoplasmic membranes and in the membranes of actively growing cells (in vivo labeling). A total of 20 strains isolated from different geographic locales showed the same pattern of three major PBPs, which had molecular weights of approximately 90,000, 63,000, and 48,000. Five clinical isolates of intrinsically penicillin-resistant gonococci each exhibited reduced penicillin binding of PBPs 1 and 2. The construction of an isogenic set of transformants with increasing levels of penicillin resistance indicated that the penA gene was associated with a decrease in penicillin binding fo PBP 2. Decreased binding to PBP 1 is likely to accompany the newly reported pem and tem genes, which govern to highest level of penicillin resistance.


Electrophysiological observations on the action of the purified scorpion venom, tityustoxin, on nerve and skeletal muscle of the rat.
When tityustoxin (TsTX, 1.43 muM; mol. wt. 6995) was applied to the rat phrenic nerve-diaphragm muscle preparation, both the directly and indirectly elicited muscle contractions were transiently potentiated by about 30 and 60%, respectively, and the half-relaxation time was prolonged to more than 10 times the control. The onset of potentiation of muscle contraction was immediate and coincided closely with the prolongation of the directly elicited action potential and depolarization of the muscle membrane but preceded the presynaptic effect of the toxin. TsTX antagonized the neuromuscular blockade produced by low concentrations of d-tubocurarine (6.5 muM) but not by higher concentrations of d-tubocurarine (13 muM) or by alpha-bungarotoxin (5 mug/ml). Single shocks to the nerve of toxin-treated muscles evoked repetitive end-plate potentials which summated and triggered action potentials and muscle contractions 15 minutes after exposure. After 25 minutes, the frequency of spontaneous transmitter release transiently increased from 2 to 550 sec-1 but was never blocked and there was no blockade of the acetylcholine receptors of chronically denervated muscle. Both the increase in miniature end-plate potential frequency and postsynaptic depolarization induced by TsTX could be blocked by tetrodotoxin, and the effects on end-plate potentials and action potentials could be blocked by lowering the external sodium concentration. Removal of calcium and addition of ethylene glycol bis (beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA, 10 mM) to the bathing fluid blocked the presynaptic but not postsynaptic effects of TsTX at 23 degrees C; at 37 degrees C the presynaptic effects of TsTX in a calcium-free medium with EGTA were depressed but still present. Delayed rectification and membrane electrical characteristics were unaffected by TsTX. The results indicate that TsTX depolarizes the pre- and postsynaptic membranes by increasing sodium permeability. The postsynaptic site of action is most likely to be the sarcolemmal membrane where TsTX delays Na inactivation and thus prolongs the active phase of muscle contraction. Presynaptically, TsTX has two sites of action: 1) it depolarizes the nerve terminal thus facilitating the spontaneous release of transmitter; and 2) it acts at the membrane of the unmyelinated nerve terminal arborizations where it prolongs the sodium current thus giving rise to a repetitive response to single shocks applied to the nerve.


Poly(vinylpyrrolidone)/KF electrolyte membranes for facilitated CO(2) transport.
In this study, we show for the first time that potassium fluoride (KF) can be utilized as a carrier for facilitated CO2 transport. A polymer electrolyte membrane was prepared by incorporating KF through coordinate covalent bonding with the amide groups of poly(vinylpyrrolidone) (PVP). The resulting PVP/KF electrolyte membrane showed enhanced CO2 separation performance compared with neat PVP. The selectivity ratio CO2/N2 increased to 4.1 with a CO2 permeance of 28 GPU. This enhanced separation performance was attributable to the reversible interaction of KF with CO2 molecules, resulting in the increase of CO2 transport. The interaction between KF and the amide groups of PVP was confirmed by FT-IR spectroscopy and X-ray photoelectron spectroscopy (XPS). The coordination of potassium ions with the amide groups caused the free ions in KF to be increased, resulting in the favorable interaction with CO2 molecules.


Physical activity and endometrial cancer risk: a review of the current evidence, biologic mechanisms and the quality of physical activity assessment methods.
To (1) determine the nature of the association between physical activity and endometrial cancer risk; (2) assess the contribution of variation in the quality of physical activity measurement to inconsistencies in study results; and (3) review the biologic mechanisms that might mediate possible effects of physical activity on risk. We reviewed and summarized all published epidemiologic studies examining physical activity and endometrial cancer risk, and evidence relating to possible biologic mechanisms. We assigned each study a quality score for physical activity measurement. Fourteen of the 18 studies showed a convincing or possible protective effect of physical activity on endometrial cancer risk, with an average relative risk reduction of around 30%. A dose-response relation was observed in 7 of 13 studies. The quality score was not related to the observed strength of association or the presence of a dose-response relation. There was epidemiologic and biologic evidence that vigorous activity, as well as light and moderate intensity activities, such as housework, gardening or walking for transportation, may reduce risk. Physical activity probably has a protective role in endometrial cancer development. More epidemiologic and biologic evidence is needed to make conclusive recommendations on optimal types, characteristics or time periods of physical activity.


Air monitoring of volatile organic compounds at relevant receptors during hydraulic fracturing operations in Washington County, Pennsylvania.
A 3-month air monitoring study was conducted in Washington County, Pennsylvania, at the request of local community members regarding the potential risks resulting from air emissions of pollutants related to hydraulic fracturing operations. Continuous air monitoring for total volatile organic compounds was performed at two sampling sites, including a school and a residence, located within 900 m of a hydraulic fracturing well pad that had been drilled prior to the study. Intermittent 24-hour air samples for 62 individual volatile organic compounds were also collected. The ambient air at both sites was monitored during four distinct periods of unconventional natural gas extraction activity: an inactive period prior to fracturing operations, during fracturing operations, during flaring operations, and during another inactive period after operations. The results of the continuous monitoring during fracturing and flaring sampling periods for total volatile organic compounds were similar to the results obtained during inactive periods. Total volatile organic compound 24-hour average concentrations ranged between 0.16 and 80 ppb during all sampling periods. Several individual volatile compounds were detected in the 24-hour samples, but they were consistent with background atmospheric levels measured previously at nearby sampling sites and in other areas in Washington County. Furthermore, a basic yet conservative screening level evaluation demonstrated that the detected volatile organic compounds were well below health-protective levels. The primary finding of this study was that the operation of a hydraulic fracturing well pad in Washington County did not substantially affect local air concentrations of total and individual volatile organic compounds.


The Novel PIM1 Inhibitor NMS-P645 Reverses PIM1-Dependent Effects on TMPRSS2/ERG Positive Prostate Cancer Cells And Shows Anti-Proliferative Activity in Combination with PI3K Inhibition.
PIM1 is over-expressed in multiple tumors, including prostate cancer (PCa). PIM1 upregulation is mediated by direct binding of the ERG transcription factor to its promoter. About 50% of PCa cases are characterized by the presence of the TMPRSS2/ERG fusion, leading to ERG over-expression and thus to PIM1 transcriptional activation. PIM kinases are considered as weak oncogenes, but when combined with additional genetic alterations can induce strong transforming effects. Here we show anti-proliferative activity of the newly described PIM1 inhibitor NMS-P645 in combination with the PI3K inhibitor GDC-0941 in TMPRSS2/ERG positive and negative PCa cells. Treatment with NMS-P645 alone can reverse PIM1-mediated pro-survival signals in prostate cells, such as activation of STAT3 through Tyr705 phosphorylation and resistance to taxane-based treatments, but does not exert a strong anti-tumoral effect. However, the simultaneous treatment with NMS-P645 and GDC-0941 induces a significant anti-proliferative response in PCa cells. These results support the use of combination strategies with PIM and PI3K inhibitors as effective treatment for PCa cases.


Crystalline and magnetic structure-property relationship in spinel ferrite nanoparticles.
Magnetic spinel ferrite MFe2O4 (M = Mn, Co, Ni, Zn) nanoparticles have been prepared via simple, green and scalable hydrothermal synthesis pathways utilizing sub- and supercritical conditions to attain specific product characteristics. The crystal-, magnetic- and micro-structures of the prepared crystallites have been elucidated through meticulous characterization employing several complementary techniques. Analysis of energy dispersive X-ray spectroscopy (EDS) and X-ray absorption near edge structure (XANES) data verifies the desired stoichiometries with divalent M and trivalent Fe ions. Robust structural characterization is carried out by simultaneous Rietveld refinement of a constrained structural model to powder X-ray diffraction (PXRD) and high-resolution neutron powder diffraction (NPD) data. The structural modeling reveals different affinities of the 3d transition metal ions for the specific crystallographic sites in the nanocrystallites, characterized by the spinel inversion degree, x, [M2+1-xFe3+x]tet[M2+xFe3+2-x]octO4, compared to the well-established bulk structures. The MnFe2O4 and CoFe2O4 nanocrystallites exhibit random disordered spinel structures (x = 0.643(3) and 0.660(6)), while NiFe2O4 is a completely inverse spinel (x = 1.00) and ZnFe2O4 is close to a normal spinel (x = 0.166(10)). Furthermore, the size, size distribution and morphology of the nanoparticles have been assessed by peak profile analysis of the diffraction data, transmission electron microscopy (TEM) and scanning transmission electron microscopy (STEM). The differences in nanostructure, spinel inversion and distinct magnetic nature of the M2+ ions directly alter the magnetic structures of the crystallites at the atomic-scale and consequently the macroscopic magnetic properties of the materials. The present study serves as an important structural benchmark for the rapidly expanding field of spinel ferrite nanoparticle research.


Tannins and human health: a review.
Tannins (commonly referred to as tannic acid) are water-soluble polyphenols that are present in many plant foods. They have been reported to be responsible for decreases in feed intake, growth rate, feed efficiency, net metabolizable energy, and protein digestibility in experimental animals. Therefore, foods rich in tannins are considered to be of low nutritional value. However, recent findings indicate that the major effect of tannins was not due to their inhibition on food consumption or digestion but rather the decreased efficiency in converting the absorbed nutrients to new body substances. Incidences of certain cancers, such as esophageal cancer, have been reported to be related to consumption of tannins-rich foods such as betel nuts and herbal teas, suggesting that tannins might be carcinogenic. However, other reports indicated that the carcinogenic activity of tannins might be related to components associated with tannins rather than tannins themselves. Interestingly, many reports indicated negative association between tea consumption and incidences of cancers. Tea polyphenols and many tannin components were suggested to be anticarcinogenic. Many tannin molecules have also been shown to reduce the mutagenic activity of a number of mutagens. Many carcinogens and/or mutagens produce oxygen-free radicals for interaction with cellular macromolecules. The anticarcinogenic and antimutagenic potentials of tannins may be related to their antioxidative property, which is important in protecting cellular oxidative damage, including lipid peroxidation. The generation of superoxide radicals was reported to be inhibited by tannins and related compounds. The antimicrobial activities of tannins are well documented. The growth of many fungi, yeasts, bacteria, and viruses was inhibited by tannins. We have also found that tannic acid and propyl gallate, but not gallic acid, were inhibitory to foodborne bacteria, aquatic bacteria, and off-flavor-producing microorganisms. Their antimicrobial properties seemed to be associated with the hydrolysis of ester linkage between gallic acid and polyols hydrolyzed after ripening of many edible fruits. Tannins in these fruits thus serve as a natural defense mechanism against microbial infections. The antimicrobial property of tannic acid can also be used in food processing to increase the shelf-life of certain foods, such as catfish fillets. Tannins have also been reported to exert other physiological effects, such as to accelerate blood clotting, reduce blood pressure, decrease the serum lipid level, produce liver necrosis, and modulate immunoresponses. The dosage and kind of tannins are critical to these effects. The aim of this review is to summarize and analyze the vast and sometimes conflicting literature on tannins and to provide as accurately as possible the needed information for assessment of the overall effects of tannins on human health.


Activation of NF-κB by SOD2 promotes the aggressiveness of lung adenocarcinoma by modulating NKX2-1-mediated IKKβ expression.
Magnesium superoxide dismutase (SOD2) has been shown to cause dysfunction of p53 transcriptional activity, whereas, in turn, SOD2 expression is regulated by p53 to modulate lung tumorigenesis. In this study, we found that the level of SOD2 expression in a panel of lung cancer cells was negatively correlated with that of NK2 homeobox 1 (NKX2-1) but was not associated with p53 status. Mechanistic studies indicated that a decrease in NKX2-1 caused by SOD2-activated IKKβ transcription was achieved by derepression of binding of Sp1 to the IKKβ promoter. Immunoprecipitation, glutathione S-transferase pull-down experiments and electrophoretic mobility shift assays demonstrated a direct interaction between NKX2-1 and Sp1, blocking Sp1-mediated IKKβ transcription. SOD2-mediated nuclear factor-kappaB activation, via elevation of IKKβ transcription, promoted anchorage-independent soft-agar growth, invasion and xenograft tumor formation, because of development of the epithelial-to-mesenchymal transition. The expression level of NKX2-1 messenger RNA was negatively associated with the extent of SOD immunostaining and the IKKβ messenger RNA expression level in lung tumors. The extent of SOD2 immunostaining and IKKβ messenger RNA levels may independently predict overall survival and relapse-free survival in lung adenocarcinoma patients. In summary, we found that SOD2 activates nuclear factor-kappaB signaling by increasing IKKβ transcription, which results in progression of lung adenocarcinoma and poorer patient outcomes. We suggest that IKKβ may potentially be targeted to improve outcomes in patients with SOD2-positive tumors.


Lateralized interactive social content and valence processing within the human amygdala.
In the past, the amygdala has generally been conceptualized as a fear-processing module. Recently, however, it has been proposed to respond to all stimuli that are relevant with respect to the current needs, goals, and values of an individual. This raises the question of whether the human amygdala may differentiate between separate kinds of relevance. A distinction between emotional (vs. neutral) and social (vs. non-social) relevance is supported by previous studies showing that the human amygdala preferentially responds to both emotionally and socially significant information, and these factors might even display interactive encoding properties. However, no investigation has yet probed a full 2 (positive vs. negative valence) × 2 (social vs. non-social content) processing pattern, with neutral images as an additional baseline. Applying such an extended orthogonal factorial design, our fMRI study demonstrates that the human amygdala is (1) more strongly activated for neutral social vs. non-social information, (2) activated at a similar level when viewing social positive or negative images, but (3) displays a valence effect (negative vs. positive) for non-social images. In addition, this encoding pattern is not influenced by cognitive or behavioral emotion regulation mechanisms, and displays a hemispheric lateralization with more pronounced effects on the right side. Finally, the same valence × social content interaction was found in three additional cortical regions, namely the right fusiform gyrus, right anterior superior temporal gyrus, and medial orbitofrontal cortex. Overall, these findings suggest that valence and social content processing represent distinct kinds of relevance that interact within the human amygdala as well as in a more extensive cortical network, likely subserving a key role in relevance detection.


Motor vehicle mismatch: a national perspective.
To determine the RR of the severe injury associated with light truck vehicle (LTV) versus passenger vehicle (PV) mismatch following motor vehicle collisions across the USA. This was a retrospective cohort study with the primary outcomes of Injury Severity Score (ISS) >8 and body region Abbreviated Injury Score (AIS) >2. The National Automotive Sampling System Crashworthiness Data System (NASS CDS) was searched for occupants in frontal and side impact crashes from 1993 to 2007. Occupants in PVs struck by LTVs were compared to PV occupants struck by another PV. Poisson regression was used to estimate the RR of severe injury after adjusting for driver age, driver gender, and change in velocity during the crash (Δv). Because 21% of cases were missing Δv, multiple imputation was used to estimate the missing values. NASS CDS weights were used to estimate the risk of severe injury nationally. PV occupants in front impact crashes with an LTV as the striking vehicle were at increased risk of severe injury compared to those struck by another PV (RR 1.37, 95% CI 1.09 to 1.73). A similar increase risk was observed in side impact crashes (RR 1.34, 95% CI 1.12 to 1.62). Increased risk of injury was also identified in several body regions. Motor vehicle mismatch crashes are associated with a significant increase in risk of severe injury for PV occupants in the USA. Addressing vehicle compatibility remains an important issue for occupant safety.


Tolerance to limb tissue allografts between swine matched for major histocompatibility complex antigens.
Transplantation of limb tissue allografts would greatly expand the realm of reconstructive surgery. However, the toxicity of chronic immunosuppression has adversely tilted the risk-benefit balance for clinical transplant. In this study, a procedure was sought to achieve host tolerance to limb tissue allografts through matching of the major histocompatibility complex (MHC) antigens between donor and host swine using only a 12-day course of cyclosporine. Massachusetts General Hospital (MGH) miniature swine were used as a large animal model with defined MHC, and musculoskeletal grafts from the donor hind limb were transplanted heterotopically to the recipient femoral vessels. Allografts from MHC-mismatched donors treated with cyclosporine (n = 4) were rejected in less than 6 weeks by gross inspection and histologic sections. Allografts from MHC-matched, minor antigen mismatched donors not treated with cyclosporine (n = 4) were rejected between 9 and 12 weeks. Allografts from similarly matched donors treated with 12 days of cyclosporine (n = 7) showed no evidence of rejection until sacrifice between 25 and 47 weeks. Thus allograft tolerance was achieved between MHC-matched swine using a limited course of cyclosporine. Demonstration of limb tissue allograft survival in a large animal model without long-term immunosuppression represents an important step toward clinical transplantation.


A new method to determine mean adult height from incomplete follow-up data.
In long-term growth studies with adult height (AH) as outcome, reporting is often required while data are incomplete because some participants have not yet reached AH whereas others might be lost to follow-up. Current practice is to analyze only participants who did reach AH, which can easily give biased results. We introduce a new method into the area of growth research. We used the data of patients from a registration database and a growth study. The new method uses growth data in time intervals. The percentage of children still growing and the mean growth at each interval are used to determine mean AH. With the new method, estimated mean AHs had smaller bias and standard error than with commonly used methods. The method is not hampered by a correlation between AH and age at reaching AH, unlike methods merely using patients who have reached AH. In contrast to commonly used methods, the new method provides valid results on mean AH when complete actual measurements of AH are not (yet) available, provided that drop-out, if any, is not related to (disappointing) growth. As it also uses observed data of children with incomplete follow-up, the method employs the data more effectively.


Whole exome sequencing identifies mutations in Usher syndrome genes in profoundly deaf Tunisian patients.
Usher syndrome (USH) is an autosomal recessive disorder characterized by combined deafness-blindness. It accounts for about 50% of all hereditary deafness blindness cases. Three clinical subtypes (USH1, USH2, and USH3) are described, of which USH1 is the most severe form, characterized by congenital profound deafness, constant vestibular dysfunction, and a prepubertal onset of retinitis pigmentosa. We performed whole exome sequencing in four unrelated Tunisian patients affected by apparently isolated, congenital profound deafness, with reportedly normal ocular fundus examination. Four biallelic mutations were identified in two USH1 genes: a splice acceptor site mutation, c.2283-1G>T, and a novel missense mutation, c.5434G>A (p.Glu1812Lys), in MYO7A, and two previously unreported mutations in USH1G, i.e. a frameshift mutation, c.1195_1196delAG (p.Leu399Alafs*24), and a nonsense mutation, c.52A>T (p.Lys18*). Another ophthalmological examination including optical coherence tomography actually showed the presence of retinitis pigmentosa in all the patients. Our findings provide evidence that USH is under-diagnosed in Tunisian deaf patients. Yet, early diagnosis of USH is of utmost importance because these patients should undergo cochlear implant surgery in early childhood, in anticipation of the visual loss.


Effect of GM1 ganglioside after focal cerebral ischemia in halothane-anesthetized cats.
The effect of the ganglioside GM1 was studied in a focal cerebral ischemia model in 30 cats consisting of 2 hours of middle cerebral artery occlusion followed by 4 hours of recirculation. The cerebrocortical electrical activity, extracellular potassium activity, and microcirculation indicated by NAD/NADH fluorescence were measured during occlusion as well as during recirculation in the core of the middle cerebral artery territory, while the cerebral metabolic rate for glucose (ICMRgl) was measured at the end of recirculation. The cats were classified into either mildly or moderately severe stroke groups based on the depression of the cerebrocortical electrical activity on the occluded side. Of 12 cats with only a mild stroke, six were administered GM1 intravenously 30 minutes after occlusion, while six cats were not treated. Of 12 cats with a moderate stroke, six were treated and six were left untreated. In six additional cats, only a sham insult was undertaken. In the cats with mild stroke, GM1 treatment significantly increased lCMRgl in the peripheral middle cerebral artery territory compared with the untreated cats; for the six treated cats, lCMRgl was normalized toward the control level, whereas it was depressed in the six untreated cats. There were no other significant effects of GM1 treatment on the other measured parameters. A potential protective effect of anesthesia is discussed.


Role of Markov Modeling Approaches to Understand the Impact of Infertility Treatments.
We are proposing to use Markov modeling type of analysis to understand data generated by treatments for infertility in women receiving ovarian stimulations. We describe the conceptual novelties, need for such an analysis, basics of the proposed methods, and theoretical constructions of various probabilities associated with practical level implementation of the Markov modeling procedures. This method can be adopted to infertility-related data visualizations whenever progression of outcome stages in infertility treatment is recorded. These methods if implemented should be able to enhance the understanding of treatment impacts of gonadotropins, clomiphene citrate, or an aromatase inhibitor at the beginning of treatment cycles of infertile women. This framework will be very useful for infertility treatment practitioners to compute the values of success rates of treatment for total population or population divided by demographic, clinical, and genetic factors. These methods can be continuously updated with newer data and translated into a mobile app to be used by clinical practitioners.


Beyond the root: dilatation of the distal aorta in Marfan's syndrome.
To investigate dilatory changes of the aorta distal to the root in patients with Marfan's syndrome. Data of 268 patients with Marfan's syndrome who were enrolled in the Euro Heart Survey on adult congenital heart disease were analysed. Data used for this study were baseline characteristics, diameters at four levels of the aorta and events during follow up (dissection, aortic repairs and death). At inclusion, 26 patients had a previous dissection and 53 patients without a previous dissection had undergone elective aortic repair, thus leaving 189 patients without previous dissection or repair. During follow up (median 5.4 years), four patients died. A total of 46 aortic events (dissection or elective surgery) occurred in 45 patients, in the distal aorta in 14 patients (31%). Baseline aortic diameter at the levels distal to the root (arch, descending aorta and abdominal aorta) was greater in patients with than in those without a previous elective aortic root intervention (median 26 mm v 24 mm, p = 0.01; 25 mm v 20 mm, p < 0.01; and 20 mm v 17 mm, p < 0.01, respectively). Multivariate analysis showed that a previous elective aortic intervention was associated with a fourfold increased probability of dilatation of the distal aorta, after adjustment for age and sex (p < 0.01). In patients without a previous intervention, the baseline diameter of the descending aorta was an independent predictor of aortic events (hazard ratio 3.0 per quartile, 95% CI 1.5 to 5.9, p = 0.002). Cause for concern is that complete measurements of the aorta (at least one measurement at each level at baseline or during follow up) were available for only 38% of the patients. Almost one in every three aortic events occurring during follow up of these patients involved the distal aorta. After elective aortic root replacement, a dilated distal aorta is more common than before. Moreover, an increased diameter of the descending aorta is associated with a higher risk of aortic events in patients without previous dissection or aortic root replacement, independent of the diameter of the aortic root. Careful monitoring of the entire aorta is essential for the optimal management of patients with Marfan's syndrome, especially after elective surgery, but is insufficiently performed in Europe.


Cancer Signature Investigation: ERBB2 (HER2)-Activating Mutation and Amplification-Positive Breast Carcinoma Mimicking Lung Primary.
Next-generation sequencing of primary and metachronous metastatic cancer lesions may impact patient care. We present a case of relapsed metastatic breast cancer with a dominant pulmonary lesion originally identified as lung adenocarcinoma. A 72-year-old, never-smoker woman with a protracted cough was found to have a large lung mass and regional lymphadenopathy on a chest CT. Lung mass biopsy showed adenocarcinoma with focal TTF-1 (thyroid transcription factor 1) positivity, favoring a lung primary. In addition to stereotactic brain radiation for cerebral metastases, she was started on carboplatin/pemetrexed. As part of the workup, the tumor was analyzed by a 50-gene targeted mutation panel, which detected 3 somatic mutations: ERBB2 (HER2) D769H activating missense mutation, TP53 Y126 inactivating truncating mutation, and SMARCB1 R374Q missense mutation. Of note, the patient had a history of stage IIA triple-negative grade 3 invasive ductal carcinoma of the left breast 1.5 years ago and received neoadjuvant chemotherapy and adjuvant radiation, and underwent a lumpectomy. Further analysis of her primary breast tumor showed a mutational profile identical to that of the lung tumor. Fluorescence in situ hybridization revealed HER2 amplification in the lung tumor, with a HER2/CEP17 ratio of 3.9. The patient was diagnosed with recurrent HER2-positive metastatic breast carcinoma with a coexisting ERBB2 (HER2) activating mutation. Chemotherapy was adjusted to include dual HER2-targeted therapy containing trastuzumab and pertuzumab, resulting in an ongoing partial response. This case demonstrates that a unique genetic mutational profile can clarify whether a tumor represents a metastatic lesion or new malignancy when conventional morphological and immunohistochemical methods are indeterminate, and can directly impact treatment decisions.


The cost-effectiveness of the MobileMums intervention to increase physical activity among mothers with young children: a Markov model informed by a randomised controlled trial.
To determine the cost-effectiveness of the MobileMums intervention. MobileMums is a 12-week programme which assists mothers with young children to be more physically active, primarily through the use of personalised SMS text-messages. A cost-effectiveness analysis using a Markov model to estimate and compare the costs and consequences of MobileMums and usual care. This study considers the cost-effectiveness of MobileMums in Queensland, Australia. A hypothetical cohort of over 36 000 women with a child under 1 year old is considered. These women are expected to be eligible and willing to participate in the intervention in Queensland, Australia. The model was informed by the effectiveness results from a 9-month two-arm community-based randomised controlled trial undertaken in 2011 and registered retrospectively with the Australian Clinical Trials Registry (ACTRN12611000481976). Baseline characteristics for the model cohort, treatment effects and resource utilisation were all informed by this trial. The incremental cost per quality-adjusted life year (QALY) of MobileMums compared with usual care. The intervention is estimated to lead to an increase of 131 QALYs for an additional cost to the health system of 1.1 million Australian dollars (AUD). The expected incremental cost-effectiveness ratio for MobileMums is 8608 AUD per QALY gained. MobileMums has a 98% probability of being cost-effective at a cost-effectiveness threshold of 64 000 AUD. Varying modelling assumptions has little effect on this result. At a cost-effectiveness threshold of 64 000 AUD, MobileMums would likely be a cost-effective use of healthcare resources in Queensland, Australia. Australian Clinical Trials Registry; ACTRN12611000481976.


RGO LBL modified biomimetic electrochemical sensor for detection of Sildenafil in herbal sexual health products.
In this work, a highly sensitive and selective biomimetic electrochemical sensor for Sildenafil in herbal sexual health products was prepared. Reduced graphene oxide (RGO), a novel highly conductive material was used to modify glassy carbon electrode (GCE) through layer-by-layer (LBL) self-assembly. The conductive molecularly imprinted films were constructed on the functional electrode surface using Sildenafil as template molecules, p-phenylenediamine (p-PD) as functional monomers. The obtained molecularly imprinted electrochemical sensor (MIES) was successfully used to detect Sildenafil in herbal sexual health products. The limit of detection (LOD) was 6.2 nmol L⁻¹. The recoveries for the spiked Sildenafil contents were in the range of 92.34-97.71% with the RSD < 2.31%. The selective efficiencies for Sildenafil and other structurally related analogues only slightly varied from 0.93 to 1.09.


Disclosure of a stigmatized identity: A qualitative study of the reasons why people choose to tell or not tell others about their traumatic brain injury.
To investigate what goals influence the decisions of people with a traumatic brain injury to disclose (or not to disclose) information about their brain injury. Ten people with a traumatic brain injury were interviewed about disclosing information about their injury to others. Thematic analysis was used to analyse the data. The report focuses on disclosure to people other than immediate family and close friends. Reasons for not disclosing included concern about negative reactions from others, feelings of shame about the injury, wanting to avoid getting distressed, wanting to fit in, lack of interest from others and the perception that the stress associated with the act of disclosing outweighed the benefits. Reasons for disclosing included obtaining emotional and practical support from others, the emotional release obtained from disclosure, the need to explain their behaviour to others and giving others the benefit of their experience. Experience of negative and stigmatizing reactions from others was common. Participants varied in their willingness to disclose. Disclosure can have important advantages and disadvantages. Some people with a TBI may need support in making optimal decisions about disclosure.


Detection and Confirmation of Potato mop-top virus in Potatoes Produced in the United States and Canada.
Potato mop-top virus (PMTV) was detected in potatoes grown in the United States and Canada during surveillance testing by a reverse transcription-polymerase chain reaction (RT-PCR) targeting the coat protein gene in RNA3. Out of 3,221 lots of seed and ware potatoes that were tested, 4.3% were positive for PMTV. The reliability of the survey results was confirmed by reextraction of selected samples and additional RT-PCR tests using two primer sets targeting gene segments in RNA2 and RNA3. Amplicons generated from RNA2 and RNA3 were identified by analysis of fragment length polymorphisms after digestion with BamHI and HindIII, respectively. PMTV was further identified by enzyme-linked immunosorbent assay, bioassay on Nicotiana debneyi, and transmission electron microscopy. Sequencing of a portion of the coat protein gene revealed near 100% identity among isolates from the United States and Canada and >97% homology of the North American isolates with European isolates.


Caffeic acid phenethyl ester inhibits nuclear factor-kappaB and protein kinase B signalling pathways and induces caspase-3 expression in primary human CD4+ T cells.
Caffeic acid phenethyl ester (CAPE), an active component in propolis, is known to have anti-tumour, anti-inflammatory and anti-oxidant properties. In this study, the effects of CAPE on the functions of primary human CD4+ T cells were evaluated in vitro. CAPE significantly suppressed interferon (IFN)-gamma and interleukin (IL)-5 production and proliferation of CD4+ T cells stimulated by soluble anti-CD3 and anti-CD28 monoclonal antibodies in both healthy subjects and asthmatic patients. CAPE inhibited nuclear factor (NF)-kappaB activation and protein kinase B (Akt) phosphorylation, but not p38 mitogen-activated protein kinase (MAPK) phosphorylation in T cells. CAPE also induced active caspase-3 expression in CD4+ T cells; CCR4+CD4+ T cells were more sensitive to CAPE induction than CXCR3+CD4+ T cells. Together, these results indicate that CAPE inhibits cytokine production and proliferation of T cells, which might be related to the NF-kappaB and Akt signalling pathways, and that CCR4+CD4+ T cells are more sensitive to CAPE inhibition. This study provides a new insight into the mechanisms of CAPE for immune regulation and a rationale for the use of propolis for the treatment of allergic disorders.


Insulin-like growth factors-1 and -2, but not hypoxia, synergize with gonadotropin hormone to promote vascular endothelial growth factor-A secretion by monkey granulosa cells from preovulatory follicles.
The midcycle gonadotropin surge promotes vascular endothelial growth factor-A (VEGF-A) production by granulosa cells in the ovulatory follicle, but it is unclear whether primary regulators of VEGF secretion in other tissues, including hypoxia and growth factors, are also important in the ovary. To address these issues, granulosa cells were collected from rhesus monkeys during controlled ovarian stimulation either before (i.e., nonluteinized granulosa cells, NLGCs) or 27 hours after (i.e., luteinized granulosa cells, LGCs) administration of an ovulatory bolus of hCG, and cultured in fibronectin-coated wells containing a chemically defined media. When NLGCs were transferred to various O2 environments (20%, 5%, or 0% O2) or media containing 100 mM CoCl2, LH (100 ng/ml)-stimulated progesterone (P4) levels were markedly (P < 0.05) suppressed by 0% O2 or CoCl2. VEGF concentrations also declined (P < 0.05) in control, CoCl2, and CoCl2 + LH groups in 0% O2, although CoCl2 modestly increased (75% above control; P < 0.05) VEGF levels in 20% and 5% O2. When NLGCs were cultured in the presence of recombinant human insulin-like growth factor (IGF)-1, IGF-2, or insulin, there was a dose-dependent increase (P < 0.05) in VEGF levels on Day 1 of culture. Whereas optimal doses of IGF-1 or IGF-2 (50 ng/ml), hCG (100 ng/ml), and IGF plus hCG stimulated VEGF levels on Day 1, only the combination of IGF-1 or IGF-2 plus hCG increased VEGF above controls and sustained levels through Day 3 of culture. The synergistic effects of IGF and hCG were also evident in P4 levels, and were not due to changes in DNA content between treatment groups. LGCs produced much higher levels of P4 and VEGF, but the responses to different O2 concentrations and insulin-related factors were qualitatively similar to those of NLGCs. These results suggest that hypoxia is not a primary regulator of VEGF production in primate granulosa cells. However, IGFs may act in concert with the gonadotropin surge to promote VEGF secretion in the ovulatory, luteinizing follicle.


Relations Between Narrative Coherence, Identity, and Psychological Well-Being in Emerging Adulthood.
The hypothesis that the ability to construct a coherent account of personal experience is reflective, or predictive, of psychological adjustment cuts across numerous domains of psychological science. It has been argued that coherent accounts of identity are especially adaptive. We tested these hypotheses by examining relations between narrative coherence of personally significant autobiographical memories and three psychological well-being components (i.e., purpose and meaning, positive self-view, positive relationships). We also examined the potential moderation of the relations between coherence and well-being by assessing the identity content of each narrative. We collected two autobiographical narratives of personally significant events from 103 undergraduate students and coded them for coherence and identity content. Two additional narratives about generic/recurring events were also collected and coded for coherence. We confirmed the prediction that constructing coherent autobiographical narratives is related to psychological well-being. Further, we found that this relation was moderated by the narratives' relevance to identity and that this moderation held after controlling for narrative ability more generally (i.e., coherence of generic/recurring events). These data lend strong support to the coherent narrative identity hypothesis and the prediction that unique events are a critical feature of identity construction in emerging adulthood.


Control of Globodera spp. Using Brassica juncea Seed Meal and Seed Meal Extract.
The eradication program for the potato cyst nematode (PCN), Globodera pallida, in the Northwest of the United States revolves around the use of soil fumigation. Alternative, integrated strategies are needed to continue to battle this invasive nematode. Laboratory, greenhouse, and field experiments were conducted with G. pallida and another cyst nematode found in the United States, Globodera ellingtonae, to evaluate the efficacy of a new formulated Brassica juncea seed meal extract, as well as a traditional B. juncea seed meal, as alternate eradication strategies. This is the first report on the efficacy of B. juncea seed meal extract against plant-parasitic nematodes. Rates of B. juncea seed meal greater than 2.2 t/ha and 4.5 t/ha for G. pallida and G. ellingtonae, respectively, were required for egg hatch suppression, as determined by a potato root diffusate (PRD) bioassay. Reproduction of G. pallida on potato after exposure to B. juncea seed meal at a rate of 2.2 t/ha was also significantly reduced. In the field, 8.9 t/ha B. juncea seed meal almost eliminated egg hatch of G. ellingtonae. Rates needed for Globodera spp. suppression were greatly reduced when using the B. juncea seed meal extract. When compared side-by-side, half as much B. juncea seed meal extract, 1.1 t/ha, was required to suppress G. ellingtonae egg hatch to the same extent as B. juncea seed meal. Exposure of G. pallida to B. juncea seed meal extract at 4.5 t/ha reduced egg hatch by 90% compared with a nonamended control. The ability to reduce the amount of material being applied to soil by using an extract has the potential for integration into a G. pallida eradication program.


Socioeconomic status and oppositional defiant disorder in preschoolers: parenting practices and executive functioning as mediating variables.
To investigate the mediating mechanisms of oppositional defiant disorder (ODD) in preschoolers through pathways analysis, considering the family socioeconomic status (SES) as the independent variable and the parenting style and the children's executive functioning (EF) as the mediating factors. The sample included 622 three-year-old children from the general population. Multi-informant reports from parents and teachers were analyzed. Structural Equation Modeling showed that the associations between SES, EF, parenting style and ODD levels differed by children's gender: (a) for girls, the association of low SES and high ODD scores was partially mediated by difficulties in EF inhibition, and parenting practices defined by corporal punishment and inconsistent discipline obtained a quasi-significant indirect effect into the association between SES and ODD; (b) for boys, SES and EF (inhibition and emotional control) had a direct effect on ODD with no mediation. SES seems a good indicator to identify children at high-risk for prevention and intervention programs for ODD. Girls with ODD in families of low SES may particularly benefit from parent training practices and training in inhibition control.